I. Field of the Invention
The present invention is related generally to transdermal delivery of therapeutic agents by the use of an applied electro motive force (emf), commonly known as iontophoresis. More particularly, the present invention is directed to a process for preparing single-use power sources for use in disposable, wearable forms of iontophoretic delivery devices and the power sources made by the process.
II. Related Art
The process of iontophoresis was described by LeDuc in 1908 and has since found commercial use in the delivery of ionically charged therapeutic agent molecules such as pilocarpine, lidocaine and dexamethasone. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode, while ions bearing a negative charge are driven across the skin at the site of an electrolytic system cathode.
Earlier, and some present, iontophoretic devices have been typically constructed of two electrodes attached to a patient, each connected by a wire to a remote power supply, generally a microprocessor-controlled electrical instrument. Because they involve direct patient contact with the electrodes, these devices are most conveniently constructed so as to make use of disposable electrodes, associated with a reusable electric instrument. The electrical instruments generally are battery powered and designed in a manner such that the batteries can be easily replaced as they become consumed.
More recently, self-contained wearable iontophoretic systems have been developed. These systems are advantageous in that they do not have external wires and are much smaller in size. Examples of such systems can be found in a variety of U.S. patents, including U.S. Pat. Nos. 4,927,408; 5,358,483; 5,458,569; 5,466,217; 5,533,971; 5,605,536; 5,651,768; and 5,685,837.
Depending on factors relating to cost, particular use and convenience, wearable iontophoretic systems can be xe2x80x9creusablexe2x80x9d or xe2x80x9cdisposablexe2x80x9d. Reusable systems may be defined as systems in which the power source is designed to be replaceable; whereas disposable systems may be defined as devices in which the entire iontophoretic system is designed to be disposed following a single use or consumption of the original power source.
The power sources for self-contained iontophoretic systems can further be characterized as xe2x80x9cgalvanicxe2x80x9d, xe2x80x9celectrolyticxe2x80x9d or a combination of these. xe2x80x9cGalvanicxe2x80x9d power is defined as power supplied by a couple, including a pair of electrodes having amounts of dissimilar surface electroactive materials that inherently provide a voltage difference between the electrodes (anode and cathode) and which normally are connected directly by a conductor. xe2x80x9cElectrolyticxe2x80x9d power sources are power sources generally remote from but in conductive contact with the electrodes, and usually include such devices as button-type batteries or sheet-like multi-layer elements. Electrolytic and galvanic sources of power are known in the art and describe, for example, in the above-referenced U.S. Pat. Nos. 4,927,408; 5,533,971; and 5,685,837.
With iontophoresis, the rate that medications are introduced is a function of the level of current, while the total quantity of medication delivered is a function of both current level(s) and time or the amount of total charge transferred. Because of this relation, often the quantity of medication introduced by iontophoresis is referred to in units of mA-minutes of dosage. Thus, for example, an equivalent 40 mA-minute dosage can be delivered at different rates; 0.1 mA for 400 minutes, 1 mA for 40 minutes, 10 mA for 4 minutes, etc.
Control of the dosage delivered by iontophoresis is usually accomplished by means of electrical circuitry in the form of electrical components mounted on the circuit layer. Electrical components can be utilized to regulate the level, waveform, timing and other aspects of the electrical current and the system usually includes a microprocessor adapted to control the current over time. These electrical circuits are well known and are described, for example, in U.S. Pat. No. 5,533,971.
Recently, means have been developed to regulate the total iontophoretic dosage in its delivery-time profile by precise, pre-determined control of the charge capacity of the power supply design. In this regard, reference is also made to certain other pending U.S. patent applications assigned to the same assignee as the present application. These include application Ser. No. 09/674,211, filed Oct. 26, 2000, entitled xe2x80x9cCONTROLLED DOSAGE DRUG DELIVERY SYSTEMxe2x80x9d, and application Ser. No. 09/613,984, filed Jul. 11, 2000, entitled xe2x80x9cRATE ADJUSTABLE DRUG DELIVERY SYSTEMxe2x80x9d. Both of these references deal with aspects of galvanic devices and disclose power supply designs that alone regulate iontophoretic delivery to a known, pre-determined total dosage. The systems eliminate the need for microprocessors and current control circuitry. The contents of both of these applications are deemed incorporated by reference herein for any purpose.
Although wearable, disposable systems have demonstrated a great convenience advantage, they must also incorporate high flexibility to be functionally effective; and they must be low enough in cost to be economically effective. Generally, as the size and number of components increase, the systems become less desirable as wearable systems and costs also increase. Therefore, it is a desirable goal to reduce the complexity of these devices and to design wearable systems with a minimal number of components, particularly components that can be readily mass-produced.
It is well known in manufacturing piece parts that costs are reduced by production in high volume, typically batch (or lot) quantities. However, it has been discovered that mass production of iontophoretic power supplies to affixed, pre-determined charged dosage within close tolerances is difficult to accomplish. In producing large batch quantities, there inevitably exists variability associated with the manufacturing process. Thus, for example, the actual capacity of power supplies produced and so the associated dosage produced in a manufacturing lot often deviates somewhat from the capacity intended (or xe2x80x9ctargetxe2x80x9d) dosages. This is not totally unexpected inasmuch as iontophoretic devices of the class are generally designed to optimally deliver a fixed and known charge in a range between about 0.06 and 60 coulombs, which corresponds to between 0.00000062 and 0.00062 gram equivalent weights of oxidizable or reducible species in limiting supply. Clearly, consistency at these low amounts is a challenge.
Additionally, it has been discovered that drift can occur during processing to cause a segment of a lot to deviate from the rest. For example, in building a sequence of parts which constitute a manufacturing lot, nominally between 1,000 and 1,000,000 parts, a first portion of the lot may deviate from a middle or end portion. Even when several devices are prepared in a single manufacturing step, deviations can occur between groupings.
Thus, it would be desirable to achieve a manufacturing process which can overcome such manufacturing deviations and result in power supplies of increased manufactured consistency.
The present invention provides improved process for the preparation of power sources intended to be used in iontophoretic delivery systems that are disposable, wearable and constructed so as to provide a pre-determined, known iontophoretic charged dosage. The benefits provided by the methods described by this invention make possible the production of more consistent power sources in high manufacturing volumes, thereby reducing costs. By means of this invention, a method is provided for characterizing the xe2x80x9cactualxe2x80x9d charged dosage for a production lot of iontophoresis power supplies, intended to be built to a pre-determined xe2x80x9ctargetxe2x80x9d charged dosage. Power sources can be independently used or designed to be a component along with other electrical circuitry. In the process, a test characterization is conducted on a selected sampling of a lot which furnishes results that can be extrapolated to the entirety of the lot. Methods of test characterization are provided for both electrolytic and galvanic power sources to be used in such devices.
The invention further provides a method for adjusting the capacity of iontophoretic power sources so as to make them conform to an acceptable range of charged dosage capacities. Thus, if after a lot characterization, it is determined that all or a portion of the manufactured lot fall outside of accuracy or precision specifications, the second aspect of this invention provides means to render that lot (or portion thereof) conforming to those specifications. This can involve either an increase or decrease in such capacity.
The invention also contemplates galvanic or electrolytic power sources of pre-determined charged dosage capacity and wearable iontophoretic devices which incorporate them.
Whereas a limited number of examples are utilized, it will be understood that these are meant to exemplify one or more aspects of the invention rather than to limit its scope and variations will occur to those skilled in the art upon familiarization with the specification, drawings and claims appended hereto.